tbuckley/cabot-search huggingface dataset:
Intranasal administration of <i>Acinetobacter lwoffii</i> in a murine model of asthma induces <scp>IL</scp>‐6‐mediated protection associated with cecal microbiota changes
Authors: Bilal Alashkar Alhamwe, Zhan Gao, Fahd Alhamdan, Hani Harb, Matthieu Pichene, Abel Garnier, Jihad El Andari, Andreas Kaufmann, Peter L. Graumann, Dörthe Kesper, Christian Daviaud, Holger Garn, Jörg Tost, Daniel P. Potaczek, Martin J. Blaser, Harald Renz
Journal: Allergy (2022)

Abstract Background Early‐life exposure to certain environmental bacteria including Acinetobacter lwoffii ( AL ) has been implicated in protection from chronic inflammatory diseases including asthma later in life. However, the underlying mechanisms at the immune‐microbe interface remain largely unknown. Methods The effects of repeated intranasal AL exposure on local and systemic innate immune responses were investigated in wild‐type and Il6 −/− , Il10 −/− , and Il17 −/− mice exposed to ovalbumin‐induced allergic airway inflammation. Those investigations were expanded by microbiome analyses. To assess for AL ‐associated changes in gene expression, the picture arising from animal data was supplemented by in vitro experiments of macrophage and T‐cell responses, yielding expression and epigenetic data. Results The asthma preventive effect of AL was confirmed in the lung. Repeated intranasal AL administration triggered a proinflammatory immune response particularly characterized by elevated levels of IL‐6, and consequently, IL‐6 induced IL‐10 production in CD4 + T‐cells. Both IL‐6 and IL‐10, but not IL‐17, were required for asthma protection. AL had a profound impact on the gene regulatory landscape of CD4 + T‐cells which could be largely recapitulated by recombinant IL‐6. AL administration also induced marked changes in the gastrointestinal microbiome but not in the lung microbiome. By comparing the effects on the microbiota according to mouse genotype and AL ‐treatment status, we have identified microbial taxa that were associated with either disease protection or activity. Conclusion These experiments provide a novel mechanism of Acinetobacter lwoffii ‐induced asthma protection operating through IL‐6‐mediated epigenetic activation of IL‐10 production and with associated effects on the intestinal microbiome.
Topical reinforcement of the cervical mucus barrier to sperm
Authors: Ulrike Schimpf, Erika Caldas-Silveira, Ljudmila Katchan, Cécile Vigier-Carriere, Isabelle Lantier, Gilai Nachmann, Sebastian Gidlöf, Aino Fianu Jonasson, Lars Björndahl, Stéphane Trombotto, Xavier Druart, Thomas Crouzier
Journal: Science Translational Medicine (2022)

Close to half of the world’s pregnancies are still unplanned, reflecting a clear unmet need in contraception. Ideally, a contraceptive would provide the high efficacy of hormonal treatments, without systemic side effects. Here, we studied topical reinforcement of the cervical mucus by chitosan mucoadhesive polymers as a form of female contraceptive. Chitosans larger than 7 kDa effectively cross-linked human ovulatory cervical mucus to prevent sperm penetration in vitro. We then demonstrated in vivo using the ewe as a model that vaginal gels containing chitosan could stop ram sperm at the entrance of the cervical canal and prevent them from reaching the uterus, whereas the same gels without chitosan did not substantially limit sperm migration. Chitosan did not affect sperm motility in vitro or in vivo, suggesting reinforcement of the mucus physical barrier as the primary mechanism of action. The chitosan formulations did not damage or irritate the ewe vaginal epithelium, in contrast to nonoxynol-9 spermicide. The demonstration that cervical mucus can be reinforced topically to create an effective barrier to sperm may therefore form the technological basis for muco-cervical barrier contraceptives with the potential to become an alternative to hormonal contraceptives.
Study design considerations for trials to evaluate multicancer early detection assays for clinical utility
Authors: Lori M Minasian, Paul Pinsky, Hormuzd A Katki, Tony Dickherber, Paul K J Han, Lyndsay Harris, Christos Patriotis, Sudhir Srivastava, Carol J Weil, Philip C Prorok, Philip E Castle
Journal: JNCI Journal of the National Cancer Institute (2022)

Abstract Blood-based assays using various technologies and biomarkers are in commercial development for the purpose of detecting multiple cancer types concurrently at an early stage of disease. These multicancer early detection (MCED) assays have the potential to improve the detection of cancers, particularly those for which no current screening modality exists. However, the unknown clinical benefits and harms of using MCED assays for cancer screening necessitate the development and implementation of a randomized controlled trial (RCT) to ascertain their clinical effectiveness. This was the consensus of experts at a National Cancer Institute–hosted workshop to discuss initial design concepts for such a trial. Using these assays to screen simultaneously for multiple cancers poses novel uncertainties for patient care compared with conventional screening tests for single cancers, such as establishing the diagnostic workup to confirm the presence of cancer at any organ site; clarifying appropriate follow-up for a positive assay for which there is no definitive diagnosis; identifying potential harms such as overdiagnosis of indolent disease; determining clinically effective and efficient strategies for disseminating MCED screening in real-world practice; and understanding the ethical implications, such as potentially alleviating or exacerbating existing health disparities. These assays present new and complex challenges for designing an RCT. Issues that emerged from the meeting centered around the need for a flexibly designed, clinical utility RCT to rigorously capture the evidence required to fully understand the net benefit of this promising technology. Specific topic areas were endpoints, screening protocols, recruitment, diagnostic pathway, pilot phase, data elements, specimen collection, and ethical considerations.
AKR1C3-dependent lipid droplet formation confers hepatocellular carcinoma cell adaptability to targeted therapy
Authors: Changqing Wu, Chaoliu Dai, Xinyu Li, Mingju Sun, Hongwei Chu, Qiuhui Xuan, Yalei Yin, Chengnan Fang, Fan Yang, Zhonghao Jiang, Qing Lv, Keqing He, Yiying Qu, Baofeng Zhao, Ke Cai, Shuijun Zhang, Ran Sun, Guowang Xu, Lihua Zhang, Siyu Sun, Yang Liu
Journal: Theranostics (2022)

Rationale: Increased lipid droplet (LD) formation has been linked to tumor metastasis, stemness, and chemoresistance in various types of cancer. Here, we revealed that LD formation is critical for the adaptation to sorafenib in hepatocellular carcinoma (HCC) cells. We aim to investigate the LD function and its regulatory mechanisms in HCC. Methods: The key proteins responsible for LD formation were screened by both metabolomics and proteomics in sorafenib-resistant HCC cells and further validated by immunoblotting and immunofluorescence staining. Biological function of AKR1C3 was evaluated by CRISPR/Cas9-based gene editing. Isotopic tracing analysis with deuterium3-labeled palmitate or carbon13-labeled glucose was conducted to investigate fatty acid (FA) and glucose carbon flux. Seahorse analysis was performed to assess the glycolytic flux and mitochondrial function. Selective AKR1C3 inhibitors were used to evaluate the effect of AKR1C3 inhibition on HCC tumor growth and induction of autophagy. Results: We found that long-term sorafenib treatment impairs fatty acid oxidation (FAO), leading to LD accumulation in HCC cells. Using multi-omics analysis in cultured HCC cells, we identified that aldo-keto reductase AKR1C3 is responsible for LD accumulation in HCC. Genetic loss of AKR1C3 fully depletes LD contents, navigating FA flux to phospholipids, sphingolipids, and mitochondria. Furthermore, we found that AKR1C3-dependent LD accumulation is required for mitigating sorafenib-induced mitochondrial lipotoxicity and dysfunction. Pharmacologic inhibition of AKR1C3 activity instantly induces autophagy-dependent LD catabolism, resulting in mitochondrial fission and apoptosis in sorafenib-resistant HCC clones. Notably, manipulation of AKR1C3 expression is sufficient to drive the metabolic switch between FAO and glycolysis. Conclusions: Our findings revealed that AKR1C3-dependent LD formation is critical for the adaptation to sorafenib in HCC through regulating lipid and energy homeostasis. AKR1C3-dependent LD accumulation protects HCC cells from sorafenib-induced mitochondrial lipotoxicity by regulating lipophagy. Targeting AKR1C3 might be a promising therapeutic strategy for HCC tumors.
Gene editing of human iPSCs rescues thrombophilia in hereditary antithrombin deficiency in mice
Authors: Liang V. Tang, Yanyi Tao, Yuanzheng Feng, Jiewen Ma, Wenyi Lin, Yuyang Zhang, Yi Zhang, Tingting Wu, Yaohua Cai, Hui Lu, Jun Wei, Javier Corral, Yu Hu
Journal: Science Translational Medicine (2022)

Hereditary antithrombin deficiency is caused by SERPINC1 gene mutations and predisposes to recurrent venous thromboembolism that can be life-threatening. Therefore, lifelong anticoagulation is required, which has side effects and may not be effective. In this study, peripheral blood mononuclear cells from a patient with severe antithrombin deficiency were reprogrammed into induced pluripotent stem cells (iPSCs). The mutation was corrected using CRISPR-Cas9 and Cre/LoxP genome editing. iPSCs were differentiated into hepatocytes, which were injected into the spleen of antithrombin knockout mice to restore the activity of antithrombin and reduce the thrombophilic state. Human iPSC-differentiated hepatocytes colonized mice and secreted antithrombin stably, normalizing antithrombin in plasma (activity: from 46.8 ± 5.7% to 88.6 ± 7.6%, P &lt; 0.0001; antigen: from 146.9 ± 19.5 nanograms per milliliter to 390.7 ± 16.1 nanograms per milliliter, P &lt; 0.0001). In venous thrombosis model, the rate of thrombosis in mice treated with edited hepatocytes, parental hepatocytes, and wild-type mice were 60, 90, and 70%, respectively. The thrombus weight was much lighter in mice treated with edited hepatocytes compared with parental hepatocytes (7.25 ± 2.00 milligrams versus 15.32 ± 2.87 milligrams, P = 0.0025) and showed no notable difference compared with that in wild-type mice (10.41 ± 2.91 milligrams). The activity and concentration of antithrombin remained high for 3 weeks after injection. The liver and kidney function markers showed no obvious abnormality during the observation period. This study provides a proof of principle for correction of mutations in patient-derived iPSCs and potential therapeutic applications for hereditary thrombophilia.
Respiratory effort during sleep and prevalent hypertension in obstructive sleep apnoea
Authors: Jean-Benoit Martinot, Nhat-Nam Le-Dong, Atul Malhotra, Jean-Louis Pépin
Journal: European Respiratory Journal (2022)

Background Mechanisms underlying blood pressure changes in obstructive sleep apnoea (OSA) are incompletely understood. Increased respiratory effort is one of the main features of OSA and is associated with sympathetic overactivity, leading to increased vascular wall stiffness and remodelling. This study investigated associations between a new measure of respiratory effort (percentage of total sleep time spent with increased respiratory effort based on measurement of mandibular jaw movements (MJM): REMOV, %TST) and prevalent hypertension in adults referred for evaluation of suspected OSA. Methods A machine learning model was built to predict hypertension from clinical data, conventional polysomnography (PSG) indices and MJM-derived parameters (including REMOV). The model was evaluated in a training subset and a test subset. Results The analysis included 1127 patients: 901 (80%) in the training subset and 226 (20%) in the test subset. The prevalence of hypertension was 31% and 30%, respectively, in the training and test subsets. A risk stratification model based on 18 input features including REMOV had good accuracy for predicting prevalent hypertension (sensitivity 0.75 and specificity 0.83). Using the Shapley additive explanation method, REMOV was the best predictor of hypertension after clinical risk factors (age, sex, body mass index and neck circumference) and time with oxygen saturation &lt;90%, ahead of standard PSG metrics (including the apnoea–hypopnoea index and oxygen desaturation index). Conclusion The proportion of sleep time spent with increased respiratory effort automatically derived from MJM was identified as a potential new reliable metric to predict prevalent hypertension in patients with OSA.
Generation and multiomic profiling of a<i>TP53/CDKN2A</i>double-knockout gastroesophageal junction organoid model
Authors: Hua Zhao, Yulan Cheng, Andrew Kalra, Ke Ma, Yueyuan Zheng, Benjamin Ziman, Caitlin Tressler, Kristine Glunde, Eun Ji Shin, Saowanee Ngamruengphong, Mouen Khashab, Vikesh Singh, Robert A. Anders, Simran Jit, Nicolas Wyhs, Wei Chen, Xu Li, De-Chen Lin, Stephen J. Meltzer
Journal: Science Translational Medicine (2022)

Inactivation of the tumor suppressor genes tumor protein p53 ( TP53 ) and cyclin-dependent kinase inhibitor 2A ( CDKN2A ) occurs early during gastroesophageal junction (GEJ) tumorigenesis. However, because of a paucity of GEJ-specific disease models, cancer-promoting consequences of TP53 and CDKN2A inactivation at the GEJ have not been characterized. Here, we report the development of a wild-type primary human GEJ organoid model and a CRISPR-edited transformed GEJ organoid model. CRISPR-Cas9–mediated TP53 and CDKN2A knockout ( TP53/CDKN2A KO ) in GEJ organoids induced morphologic dysplasia and proneoplastic features in vitro and tumor formation in vivo. Lipidomic profiling identified several platelet-activating factors (PTAFs) among the most up-regulated lipids in CRISPR-edited organoids. PTAF/PTAF receptor (PTAFR) abrogation by siRNA knockdown or a pharmacologic inhibitor (WEB2086) reduced proliferation and other proneoplastic features of TP53/CDKN2A KO GEJ organoids in vitro and tumor formation in vivo. In addition, murine xenografts of Eso26, an established human esophageal adenocarcinoma cell line, were suppressed by WEB2086. Mechanistically, TP53/CDKN2A dual inactivation disrupted both the transcriptome and the DNA methylome, likely mediated by key transcription factors, particularly forkhead box M1 (FOXM1). FOXM1 activated PTAFR transcription by binding to the PTAFR promoter, further amplifying the PTAF-PTAFR pathway. Together, these studies established a robust model system for investigating early GEJ neoplastic events, identified crucial metabolic and epigenomic changes occurring during GEJ model tumorigenesis, and revealed a potential cancer therapeutic strategy. This work provides insights into proneoplastic mechanisms associated with TP53/CDKN2A inactivation in early GEJ neoplasia, which may facilitate early diagnosis and prevention of GEJ neoplasms.
Amplification of Inflammation by Lubricin Deficiency Implicated in Incident, Erosive Gout Independent of Hyperuricemia
Authors: Khaled Elsaid, Tony R. Merriman, Leigh‐Ana Rossitto, Ru Liu‐Bryan, Jacob Karsh, Amanda Phipps‐Green, Gregory D. Jay, Sandy Elsayed, Marwa Qadri, Marin Miner, Murray Cadzow, Talia J. Dambruoso, Tannin A. Schmidt, Nicola Dalbeth, Ashika Chhana, Jennifer Höglund, Majid Ghassemian, Anaamika Campeau, Nancy Maltez, Niclas G. Karlsson, David J. Gonzalez, Robert Terkeltaub
Journal: Arthritis & Rheumatology (2022)

In gout, hyperuricemia promotes urate crystal deposition, which stimulates the NLRP3 inflammasome and interleukin-1β (IL-1β)-mediated arthritis. Incident gout without background hyperuricemia is rarely reported. To identify hyperuricemia-independent mechanisms driving gout incidence and progression, we characterized erosive urate crystalline inflammatory arthritis in a young female patient with normouricemia diagnosed as having sufficient and weighted classification criteria for gout according to the American College of Rheumatology (ACR)/EULAR gout classification criteria (the proband).
Decitabine Versus Hydroxyurea for Advanced Proliferative Chronic Myelomonocytic Leukemia: Results of a Randomized Phase III Trial Within the EMSCO Network
Authors: Raphael Itzykson, Valeria Santini, Sylvain Thepot, Lionel Ades, Cendrine Chaffaut, Aristoteles Giagounidis, Margot Morabito, Nathalie Droin, Michael Lübbert, Rosa Sapena, Stanislas Nimubona, Jean Goasguen, Eric Wattel, Gina Zini, Jose Miguel Torregrosa Diaz, Ulrich Germing, Anna Maria Pelizzari, Sophie Park, Nadja Jaekel, Georgia Metzgeroth, Francesco Onida, Robert Navarro, Andrea Patriarca, Aspasia Stamatoullas, Katharina Götze, Martin Puttrich, Sandra Mossuto, Eric Solary, Silke Gloaguen, Sylvie Chevret, Fatiha Chermat, Uwe Platzbecker, Pierre Fenaux
Journal: Journal of Clinical Oncology (2022)

Hydroxyurea (HY) is a reference treatment of advanced myeloproliferative neoplasms. We conducted a randomized phase III trial comparing decitabine (DAC) and HY in advanced myeloproliferative chronic myelomonocytic leukemias (CMML). Newly diagnosed myeloproliferative CMML patients with advanced disease were randomly assigned 1:1 to intravenous DAC (20 mg/m2/d days 1-5) or HY (1-4 g/d) in 28-day cycles. The primary end point was event-free survival (EFS), events being death and acute myelomonocytic leukemia (AML) transformation or progression. One-hundred seventy patients received DAC (n = 84) or HY (n = 86). Median age was 72 and 74 years, and median WBC count 32.5 × 109/L and 31.2 × 109/L in the DAC and HY arms, respectively. Thirty-three percent of DAC and 31% of HY patients had CMML-2. Patients received a median of five DAC and six HY cycles. With a median follow-up of 17.5 months, median EFS was 12.1 months in the DAC arm and 10.3 months in the HY arm (hazard ratio [HR], 0.83; 95% CI, 0.59 to 1.16; P = .27). There was no significant interaction between treatment effect and blast or platelet count, anemia, CMML Prognostic Scoring System, Groupe Francophone des Myelodysplasies, or CMML Prognostic Scoring System-mol risk. Fifty-three (63%) DAC patients achieved a response compared with 30 (35%) HY patients (P = .0004). Median duration of response was similar in both arms (DAC, 16.3 months; HY, 17.4 months; P = .90). Median overall survival was 18.4 months in the DAC arm and 21.9 months in the HY arm (P = .67). Compared with HY, DAC significantly reduced the risk of CMML progression or transformation to acute myelomonocytic leukemia (cause-specific HR, 0.62; 95% CI, 0.41 to 0.94; P = .005) at the expense of death without progression or transformation (cause-specific HR, 1.55; 95% CI, 0.82 to 2.9; P = .04). Compared with HY, frontline treatment with DAC did not improve EFS in patients with advanced myeloproliferative CMML (ClinicalTrials.gov identifier: NCT02214407).
Adoptive therapy with amyloid-β specific regulatory T cells alleviates Alzheimer's disease
Authors: HyeJin Yang, Seon-Young Park, Hyunjung Baek, Chanju Lee, Geehoon Chung, Xiao Liu, Ji Hwan Lee, Byungkyu Kim, Minjin Kwon, Hyojung Choi, Hyung Joon Kim, Jae Yoon Kim, Younsub Kim, Ye-Seul Lee, Gaheon Lee, Sun Kwang Kim, Jin Su Kim, Young-Tae Chang, Woo Sang Jung, Kyung Hwa Kim, Hyunsu Bae
Journal: Theranostics (2022)

Rationale: Neuroinflammation is a primary feature of Alzheimer's disease (AD), for which an increasing number of drugs have been specifically developed. The present study aimed to define the therapeutic impact of a specific subpopulation of T cells that can suppress excessive inflammation in various immune and inflammatory disorders, namely, CD4+CD25+Foxp3+ regulatory T cells (Tregs). Methods: To generate Aβ antigen-specific Tregs (Aβ+ Tregs), Aβ 1-42 peptide was applied in vivo and subsequent in vitro splenocyte culture. After isolating Tregs by magnetic bead based purification method, Aβ+ Tregs were adoptively transferred into 3xTg-AD mice via tail vein injection. Therapeutic efficacy was confirmed with behavior test, Western blot, quantitative real-time PCR (qRT-PCR), enzyme-linked immunosorbent assay (ELISA), and immunohistochemistry staining (IHC). In vitro suppression assay was performed to evaluate the suppressive activity of Aβ+ Tregs using flow cytometry. Thy1.1+ Treg trafficking and distribution was analyzed to explore the infused Tregs migration into specific organs in an antigen-driven manner in AD mice. We further assessed cerebral glucose metabolism using 18F-FDG-PET, an imaging approach for AD biological definition. Subsequently, we evaluated the migration of Aβ+ Tregs toward Aβ activated microglia using live cell imaging, chemotaxis, antibody blocking and migration assay. Results: We showed that Aβ-stimulated Tregs inhibited microglial proinflammatory activity and modulated the microglial phenotype via bystander suppression. Single adoptive transfer of Aβ+ Tregs was enough to induce amelioration of cognitive impairments, Aβ accumulation, hyper-phosphorylation of tau, and neuroinflammation during AD pathology. Moreover, Aβ-specific Tregs effectively inhibited inflammation in primary microglia induced by Aβ exposure. It may indicate bystander suppression in which Aβ-specific Tregs promote immune tolerance by secreting cytokines to modulate immune responses during neurodegeneration. Conclusions: The administration of Aβ antigen-specific regulatory T cells may represent a new cellular therapeutic strategy for AD that acts by modulating the inflammatory status in AD.
Fungal sensing by dectin-1 directs the non-pathogenic polarization of TH17 cells through balanced type I IFN responses in human DCs
Authors: Sonja I. Gringhuis, Tanja M. Kaptein, Ester B. M. Remmerswaal, Agata Drewniak, Brigitte A. Wevers, Bart Theelen, Geert R. A. M. D’Haens, Teun Boekhout, Teunis B. H. Geijtenbeek
Journal: Nature Immunology (2022)

The non-pathogenic TH17 subset of helper T cells clears fungal infections, whereas pathogenic TH17 cells cause inflammation and tissue damage; however, the mechanisms controlling these distinct responses remain unclear. Here we found that fungi sensing by the C-type lectin dectin-1 in human dendritic cells (DCs) directed the polarization of non-pathogenic TH17 cells. Dectin-1 signaling triggered transient and intermediate expression of interferon (IFN)-β in DCs, which was mediated by the opposed activities of transcription factors IRF1 and IRF5. IFN-β-induced signaling led to integrin αvβ8 expression directly and to the release of the active form of the cytokine transforming growth factor (TGF)-β indirectly. Uncontrolled IFN-β responses as a result of IRF1 deficiency induced high expression of the IFN-stimulated gene BST2 in DCs and restrained TGF-β activation. Active TGF-β was required for polarization of non-pathogenic TH17 cells, whereas pathogenic TH17 cells developed in the absence of active TGF-β. Thus, dectin-1-mediated modulation of type I IFN responses allowed TGF-β activation and non-pathogenic TH17 cell development during fungal infections in humans.